Project Summary Aging is the greatest risk factor for the development of chronic diseases. While it is appreciated that inflammation might be a common denominator for a broad range of age-related diseases such as neurodegeneration, type 2 diabetes, atherosclerosis, pathogenic infections, and cancer, the causes for the inflammatory basis of age-related diseases remains largely unknown. Several factors were shown to contribute to the initiation and progression of chronic inflammatory responses and disease risk in the elderly, including both genetic and environmental factors such as diet, hygiene, xenobiotics, and physical activity. All of these external factors have an important commonality; they shape the community of microorganisms that reside within the gastrointestinal tract. The human intestine contains one of the highest densities of microorganisms on Earth, including more than 1,000 species of bacteria, viruses, fungi and parasites, collectively termed the microbiota. Interestingly, the microbiota of older individuals differs from that of younger adults, and elderly individuals often experience gut-associated comorbidities. First insights from model organisms have indicated a possible role for the intestinal microbiota in regulating lifespan. In this study, we will decipher the mechanisms underlying the microbial contribution to the etiology of age-associated inflammation. The main innovation of the proposed project will be the identification of microbial metabolites which influence the manifestation of age-related inflammatory disease. The intestinal microbial community exerts much of its impact on host physiology through the secretion of small molecules that modulate cellular and organismal functions of the mammalian host. We will focus on inflammation in the gastrointestinal tract and intestinal epithelial barrier function, in order to elucidate which microbiome-derived molecules modulate the development of age-associated disease. Using gnotobiotic mice, metabolite supplementation strategies, metagenomic sequencing as well as assays for in vivo intestinal epithelial cell function, we will systematically identify the most relevant microbial metabolites for age- associated susceptibility to exacerbated inflammation and their mechanisms of action. The ultimate goal of this project is to define strategies for the restoration of intestinal homeostasis at old age through modulation of metabolite abundances. This study will initiate a new field of investigation based on the systematic exploration of intestinal metabolites and their contribution to age-related disease.